Not Applicable.
Not Applicable.
A variety of hydrogel-type preparations have been developed to effect the sustained release of orally ingested drugs. For example, Japanese patent application JP-A-62-120315 discloses a preparation obtained by compression-molding a drug, a hydrogel-forming water-soluble polymer and an enteric coating. JP-A-63-215620 discloses a hydrogel-type preparation with a core having a drug and a water-soluble polymer and an outer layer with a water-soluble polymer as a base. JP-B-40-2053 discloses a sustained-release preparation having a mixture of a drug and a high polymer of ethylene oxide and, as an optional component, a hydrophilic substance. However, all of these preparations are designed to release a drug continuously while the administered preparation is still retained in the upper digestive tract, typically in the stomach and small intestine. They were not intended to provide for a release of a drug in the lower digestive tract including the colon, where little water is available.
Hydrophilic gel-forming preparations have been further developed so that they can provide a sustained release of orally ingested drugs throughout the digestive system, including in the lower digestive tract. For example, EP 0 661 045 describes a preparation adapted to absorb water into its core to undergo substantially complete gelation during its stay in the upper digestive tract. As the tablet moves down the digestive system in the form of a gel to the lower digestive tract, the preparation swells and the gelled outer surface of the tablet erodes gradually releasing the drug. This type of oral tablet is capable of providing a sustained release of the drug throughout the digestive tract, including in the colon.
While the gel-forming preparations, such as those described in the EP 0 661 045, have many applications, they may not be suitable for certain types of active agents, particularly when the active agents are unstable in the gel-forming preparations or may be released in a manner that is not desirable. Thus, there exists a continuing need for improved forms of sustained release preparations which can continuously release an active agent throughout the digestive tract, regardless of the physical or chemical properties of the active agent. Moreover, many situations may require that an active agent be delivered to the patient in a non-random or pulsatile manner, or, that the active agent be delivered to a particular anatomic compartment, e.g., the colon. For example, if an easily degradable drug or a drug with a short biological half-life needs to be delivered to the colon, it cannot be released in the upper digestive tract. Thus, there is a need for tablets that are capable of providing delayed and/or pulsatile release of an active agent. The present invention fulfills these and other needs.
The present invention provides, for the first time, a tablet and methods for making the tablet that comprises a gel-forming material and at least one particle comprising an active agent in contact with a coating material to modify release of the active agent from the tablet. These particles that comprise the active agent and the coating material are also referred to as xe2x80x9cactive agent-containing particlexe2x80x9d, xe2x80x9ccoated particlexe2x80x9d or xe2x80x9ccoated bead.xe2x80x9d The gel-forming material forms a matrix (a xe2x80x9cgel-forming matrixxe2x80x9d) for the active agent-containing particles. The active agent-containing particle is formulated with a coating material so that it can modify or control the release of the active agent by, for example, slowing or inhibiting the passage of the active agent out of the tablet and into the digestive system. These tablets are also referred to as OCAS(trademark) (oral controlled absorption system) matrix tablets herein.
In some embodiments of the invention, the release of the active agent from the tablet can be modified and controlled by the combination of two systems: 1) the gel-forming matrix; and 2) the coating material in contact with the active agent. In the digestive system, the gel-forming matrix absorbs water to undergo substantially complete gelation during its stay in the upper digestive tract and moves down into the lower digestive tract undergoing constant erosion, continuously releasing the active agent-containing particles from the tablet. This erosion of the gel-forming matrix can control the release of the active agent-containing particles from the tablet. In addition to the gel-forming matrix, the coating material that is on or around the active agent provides another level of control in releasing the active agent from the tablet. For example, the coating material can modify or control the rate of diffusion of the active agent through the gel matrix and out of the tablet. Moreover, since the coating material provides a physical and/or chemical barrier for the active agent, any type of active agents can be included in the tablets of the present invention. The selection of the active agent is not restricted to those which are released from the tablet in a favorable manner.
In one aspect, the invention is particularly useful for an active agent that is hydrophilic. In the case of water insoluble or less hydrophilic active agents, the erosion of the gel-forming matrix of the tablet precedes the diffusion of the active agent through the swollen gel layer of the tablet. Thus, the active agent release rate limiting step is typically the erosion of the gel-forming matrix. Therefore, with these active agents, the gel-forming matrix alone can provide enough control on release of the active agent and can be used to design a sustained release of these active agents over, e.g., 12-24 hours. However, a hydrophilic active agent tends to diffuse out from the gel-forming matrix faster than the erosion of the swollen gel layer of the tablet. Thus, while a tablet comprising a gel-forming matrix may be useful for water insoluble or less hydrophilic active agents, the gel-forming matrix may not provide for sufficient controlled release for the hydrophilic active agent.
FIG. 9 illustrates this diffusion problem for a hydrophilic active agent. As will be described in further detail below in Example 6B, a tablet comprising Cevimeline HCl (having a high water solubility of about 766 mg/ml at 25xc2x0 C.) and a gel-forming matrix comprising a polyethylene oxide polymer (PEO) and a polyethylene glycol (PEG) was prepared. The active agent Cevimeline HCl as purchased (without further treatment) was mixed with the gel-forming material. FIG. 9 shows the drug release profile from this conventional Cevimeline HCl matrix tablet. As shown in FIG. 9, substantially all of the drug was released in about 6-8 hours from the tablet. The tablet did not provide for sustained release of the drug over, e.g., 12-24 hours.
Thus, in the embodiments of the invention, a hydrophilic active agent, such as Cevimeline HCl, is physically and/or chemically modified to control its release rate from the tablet. Preferred embodiments of the invention provide a tablet comprising a gel-forming material and a particle comprising a hydrophilic active agent, wherein the particle is formulated to modify release of the active agent from the tablet. For example, the particle comprises a hydrophilic active agent in contact with a coating material (e.g., on or around the active agent). The coating material can slow or prevent the diffusion of the hydrophilic active agent out of the gel-forming matrix.
An improvement in the release profiles of a hydrophilic drug from tablets according to embodiments of the invention are described in Example 6C and shown in FIG. 10. Example 6C describes an embodiment of the present tablet which comprises Cevimeline HCl in contact with a coating material in a gel matrx. As shown in FIG. 10, the release profiles of this modified Cevimeline HCl from the gel matrix tablet are much more gradual and linear than the release profile of unmodified Cevimeline HCl from the conventional matrix tablet shown in FIG. 9. Moreover, when FIGS. 9 and 10 are compared, it is clear that embodiments of the invention can provide a sustained release of a hydrophilic drug up to, e.g., 12-24 hours, compared to conventional gel matrix tablets without modification of the active agent.
While the above example illustrates the use of the embodiments of the invention with a hydrophilic active agent, any suitable active agents, including a less hydrophilic active agent or a hydrophobic active agent, can be incorporated into embodiments of the invention. For example, embodiments of the invention are particularly useful for active agents that are unstable, or sensitive to moisture or oxidation. As an illustration, if the active agent is an enzyme, it may lose its activity if it is in contact with water or the gel-forming material for a prolonged period of time. By providing a physical and/or chemical barrier (e.g., a coating) on or around the active agent, the active agent is protected until it is released from the tablet to the body.
As described above, these embodiments of the invention are capable of sustaining the efficacy of active agents for a prolonged period. One beneficial result is that the number of administrations can be reduced. For example, an individual needs to take a tablet comprising an active agent, such as a drug, only once a day or twice a day. In some cases, tablets can release a drug too quickly into the upper digestive tract of a person, resulting in undesirable side effects. Embodiment of the invention is capable of providing a constant concentration of the drug within the blood of a person. This may reduce potential side effects of the drug by suppressing rapid increases in blood concentration of the drug.
In another aspect, the invention provides tablets and methods for making the tablets that can achieve programmable drug release profiles. For example, the tablets can be designed to have pulsatile, delayed onset or any suitable predetermined release profile. In one embodiment, this is achieved by designing a multilayered tablet. For example, different layers of the multilayered tablet can comprise different active agents, different amounts of active agent and/or different forms of active agent. In another example, different layers of the multilayered tablet can comprise different proportions of a polymer and a gelation facilitator agent, and/or different kinds of a polymer or a gelation facilitator agent. These embodiments provide additional control of the release of the active agents from the tablet. Thus, as the multilayered tablet slowly dissolves in its passage through the digestive tract, it releases varying amounts of active agent (or different active agents) at different times, i.e., in different anatomical compartments (e.g., small intestine versus colon). This effectively allows a programmable active agent release scheme. For example, it may be desirable to release larger amounts of active agent initially (to be absorbed, e.g., in the stomach or upper end of the small intestine) while gradually releasing diminishing amounts of active agent release as the tablet passes through to the end of the colon (or vice versa). Alternatively, it may be desirable that an active agent only be released in the colon. In another embodiment, one active agent (or form of the active agent) is released in the upper digestive tract (e.g., stomach or small intestine) and another active agent or a variation of the active agent is released in the lower digestive tract (e.g., large intestine or colon).
Accordingly, in one aspect, the invention provides a tablet comprising: at least one particle comprising a hydrophilic active agent in contact with a coating material to modify release of the active agent, and a gel-forming material comprising: a polymer; and a gelation facilitator agent having a solubility higher than about 0.1 gram/ml in water at a temperature of about 20xc2x0 C.
In one embodiment, the particle comprises an active agent and a coating material on or around the active agent.
In another embodiment, the hydrophilic active agent has a water solubility of at least about 30 mg/ml at a temperature of about 25xc2x0 C.
In yet another embodiment, the hydrophilic active agent is a quinuclidine derivative or acetylcholine.
In yet another embodiment, the active agent-containing particle has a size between about 50 xcexcm to about 5 mm, preferably between about 100 xcexcm to about 3 mm, and more preferably between about 300 xcexcm to about 2 mm.
In yet another embodiment, the tablet comprises a plurality of the active agent-containing particles and wherein the gel-forming material forms a matrix for the plurality of the particles.
In yet another embodiment, the active agent is in the form of a crystal or a granule, and/or the particle comprises a plurality of active agent crystals or granules.
In yet another embodiment, the coating material slows release of the active agent from the tablet.
In yet another embodiment, the coating material is flexible.
In yet another embodiment, the coating material is selected from the group consisting of a natural polymer, a semi-synthetic polymer, and a synthetic polymer. Examples of these polymers include chitosan, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, cellulose acetate membrane, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyacrylic acid, polyvinyl acetate, poly(vinylacetate phthalate), poly(vinyl alcohol), poly(vinyl pyrrolidone), poly(lactic acid), poly(glycolic acid), poly(lactic/glycolic acid), poly(dimethyl silicone), poly(hydroxyethyl methacrylate), poly(ethylene/vinyl acetate), poly(ethylene/vinyl alcohol), or a mixture thereof.
In yet another embodiment, the coating material further comprises a plasticizer, a stabilizer or both.
In yet another embodiment, the polymer comprises a polyethylene oxide polymer.
In yet another embodiment, the gelation facilitator agent comprises a polyethylene glycol.
In yet another embodiment, the polymer to the gelation facilitator ratio is between about 1:9 to about 9:1 by weight, preferably between about 3:7 to about 7:3 by weight, more preferably between about 4:6 to about 6:4 by weight.
In yet another embodiment, the tablet has a hardness of at least about 2 kp.
In yet another embodiment, the tablet has a hardness between about 2 kp and about 10 kp.
In yet another embodiment, the tablet provides a sustained release of the active agent for at least about 12 hours.
In yet another embodiment, the tablet further comprises a non-hydrophilic active agent.
In yet another embodiment, the tablet comprises at least two different types of particles with different active agents.
In yet another embodiment, the particles in the tablet comprise at least two different types of particles with different coating materials.
In yet another embodiment, the distribution of the particles in the tablet is non-random.
In yet another embodiment, the tablet is a multilayered tablet.
In yet another embodiment, at least two of the layers of the multilayered tablet comprise a different amount of the particles or at least two different types of active agents.
In yet another embodiment, the particles in the tablet are concentrated at the core of the tablet.
In yet another embodiment, the polymer comprises a polyethylene oxide polymer and the gelation facilitator agent comprises a polyethylene glycol.
In another aspect, the invention provides a method for producing a modified tablet, the method comprising: (1) mixing a formulation comprising: (a) at least one particle comprising a hydrophilic active agent in contact with a coating material to modify release of the active agent; (b) a polymer; and (c) a gelation facilitator agent having a solubility higher than about 0.1 gram/ml in water at a temperature of about 20xc2x0 C.; and (2) compressing the formulation to produce the tablet. In these methods, any of the materials described herein can be used to produce a tablet. For example, in one embodiment of the methods, the particle comprises the active agent and a coating material on the active agent. In another example, the coating material is flexible so that it does not crack during compressing the formulation into the tablet. In yet another example, the coating material is hydrophobic.
In one embodiment of the methods, the particle is produced by spraying the coating material on the active agent.
In another embodiment, the polymer is granulated with the gelation facilitator agent in step (1).
In yet another embodiment, the polymer and the gelation facilitator agent are granulated with the active agent-containing particles in step (1).
These and other aspects of the present invention will become apparent to those skilled in the art from the following detailed description of the invention, the accompanying drawings, and the appended claims.